Analysis of Nucleotide Variations in Human G-Quadruplex Forming Regions Associated with Disease States.

While the role of G quadruplex (G4) structures has been identified in cancers and metabolic disorders, single nucleotide variations (SNVs) and their effect on G4s in disease contexts have not been extensively studied. The COSMIC and CLINVAR databases were used to detect SNVs present in G4s to identify sequence level changes and their effect on the alteration of the G4 secondary structure. A total of 37,515 G4 SNVs in the COSMIC database and 2378 in CLINVAR were identified. Of those, 7236 COSMIC (19.3%) and 457 (19%) of the CLINVAR variants result in G4 loss, while 2728 (COSMIC) and 129 (CLINVAR) SNVs gain a G4 structure. The remaining variants potentially affect the folding energy without affecting the presence of a G4. Analysis of mutational patterns in the G4 structure shows a higher selective pressure (3-fold) in the coding region on the template strand compared to the reverse strand. At the same time, an equal proportion of SNVs were observed among intronic, promoter, and enhancer regions across strands.